Presentation, progression, and predictors of ovarian insufficiency in classic galactosemia

Abstract

Classic galactosemia (CG) is an inherited metabolic disorder that affects about 1 in 50,000 live births in the United States and many other countries. With the benefit of early detection by newborn screening and rapid dietary restriction of galactose, generally achieved by removing dairy from the diet, most affected infants are spared the acute and potentially lethal symptoms of disease. Despite early detection and life-long dietary intervention, however, most patients grow to experience a constellation of long-term complications that include premature ovarian insufficiency in the vast majority of girls and young women. Our goal in the study reported here was to define the presentation, progression, and predictors of ovarian insufficiency in a cohort of 102 post-pubertal girls and women with CG. To our knowledge, this is the largest cohort studied to date. We found that 68% of the girls and women in our study achieved spontaneous menarche, while 32% achieved menarche only after starting hormone replacement therapy (HRT). Of those who achieved spontaneous menarche, fewer than 50% were still cycling regularly after 3 years, and fewer than 15% were still cycling regularly after 10 years. Of factors tested for possible association with spontaneous menarche, only detectable (≥ 0.04 ng/mL) plasma anti-Müllerian hormone (AMH) level was significant. These results extend substantially from prior studies and confirm that detectable plasma AMH is a useful predictor of ovarian function in girls and women with CG.

The natural history of classic galactosemia: lessons from the GalNet registry

“…Subsequently, POI was broadly recognized and represents a very burdensome complication for the patients and their families. The occurrence of POI in this study was comparable to previous figures [17, 30, 43, 44]. A high percentage of women with POI was taking HRT to supplement hormonal insufficiency, reflecting an appropriate follow-up.…”

Metabolic perturbations in classic galactosemia beyond the Leloir pathway: Insights from an untargeted metabolomic study

“…As illustrated, the abundance of this metabolite in cases with higher levels of AMH, indicative of more normal ovarian function, closely matched that seen in controls. However, the abundance in cases with low to undetectable AMH, indicative of premature ovarian insufficiency, was significantly higher compared to those with AMH ≥ 0.1 ng/mL (FDR = 0.0734).…”

“…Finally, we tested whether any of the metabolic features that discriminated between cases and controls in our study also distinguished among cases by outcome severity. We focused on two outcomes: (a) for all cases aged 6 years and older, whether the participant received any special educational services, including speech therapy, in elementary school, and (b) for girls and women only, whether plasma AMH, a marker of ovarian status, was <0.1 ng/mL or ≥ 0.1 ng/mL . Of note, we restricted the first outcome marker to volunteers who had received special services in elementary school to minimize potential complication from families who enrolled their preschool child in preventative intervention.…”

A galactose‐1‐phosphate uridylyltransferase‐null rat model of classic galactosemia mimics relevant patient outcomes and reveals tissue‐specific and longitudinal differences in galactose metabolism

“…However, despite early and rigorous lifelong dietary restriction of galactose, a majority of children with CG grow to experience a constellation of long‐term complications including speech, cognitive and behavioural problems, motor difficulties, and mild growth delay, among other challenges . Premature ovarian insufficiency is also common among girls and women with CG . At present, the mechanisms underlying long‐term outcomes in CG remain unclear, and there is no known intervention that prevents or resolves the long‐term sequelae of disease …”

“…1,4 Premature ovarian insufficiency is also common among girls and women with CG. 5 At present, the mechanisms underlying long-term outcomes in CG remain unclear, and there is no known intervention that prevents or resolves the long-term sequelae of disease. 3 While a variety of accessible biomarkers have been reported in CG, including differences in glycans, hormones, markers of inflammation, 6,7 and plasma metabolomic profiles, 8 perhaps the most easily and commonly followed is the accumulation of galactose metabolites.…”